15-Ethynyl-11-deoxy PGE

ABSTRACT

9-Oxo-15-substituted prostanoic acids, and intermediates for their preparation and for the preparation of other known prostaglandins are disclosed. The final products have bronchodilatory activity.

United States Patent Strike Nov. 25, 1975 I IS-ETHYNYL-l l-DEOXY PCB [56] References Cited [75] Inventor: Donald P. Strike, St. Davids. Pa. FOREIGN PATENTS OR APPLICATIONS [73] Assigneec American Home Products 2,304,706 7/l974 Germany 260/468 Corporation, New York, NY. Primary ExaminerRobert Gerstl [22] Flled' July 1973 Attorney, Agent, or Firm-Royal E. Bright [21] Appl. No.: 383,007

[57] ABSTRACT [52] 260/514 D; 260/268 R; 260/247-2 R; 9-Oxo-i5-substituted prostanoic acids, and intermedi- 26O/293-65 260/326-2? 260/468 D; ates for their preparation and for the preparation of 2605011; 260501-17;424/305i424/317 other known prostaglandins are disclosed. The final [51] Int. Cl. C07C 61/38; C07C 69/74 products have b h dfl activity [58] Field of Search 260/468 D, 514 D 2 Claims, 2 Drawing Figures US. Patent Nov.25, 1975 Sheet 1 of2 3,922,302

FIGURE I WCOOH H0 HO CH3 EDI X US. Patent N0v.25, 1975 Sheet2of2 3,922,302

1 IS-ETHYNYL-I l-DEOXY PGE BACKGROUND OF THE INVENTION I The prostaglandins are a group of hormone-like substances which may be viewed as derivatives of prostanoic acid. Several prostaglandins are found widely distributed in mammalian tissue and have been isolated from this source. These prostaglandins have been shown to possess a variety of biological properties such as bronchodilation, the ability to reduce gastric secretion, to modify muscle tone, as well as the ability to raise or lower blood pressure.

Various derivatives of prostaglandins have also been synthesized and reported. 9,l-Dihydroxy prostl3- enoic acid and methods of synthesis thereof are disclosed in US. Pat. No. 3,432,541 and 3,455,992. 9- Oxo-lS-hydroxy-l S-methyl-prostanoic acid, l5-oxo-9- hydroxy-prostanoic acid, and 9,15-dioxo prostanoic acid are disclosed in US. Pat. No. 3.67l,570.

The present invention concerns a number of new intermediates useful in the synthesis of 9-oxo-l5- hydroxy-lS-methyl-prostanoic acid as well as new unsaturated IS-methyl derivatives which are themselves useful. In addition 9-oxo-l5-hydroxy-l5-ethynyl prostanoic acids and new intermediates thereto are included.

SUMMARY OF THE INVENTION The invention sought to be patented in a first compo- 30 sition aspect resides in the concept of a chemical compound which is prostanoic acid of the structure:

wherein R is methyl, A is cisCI-I=CH and B is transCI-I=CH; R is ethynyl, A is -CH CH and B magnetic resonance, and mass spectrographic analysis, spectral data supporting the molecular structures herein set forth. The aforementioned physical characteristics, taken together with the nature of the starting materials, the mode of synthesis, and the elemental analyses, confirm the structure of the compositions sought to be patented.

The tangible embodiments of the first composition aspect of the invention possess the inherent applied use characteristic of exerting bronchodilating effects upon administration to warm-blooded animals as evidenced by pharmacological evaluation according to standard test procedures.

The invention sought to be patented in a second composition aspect resides in the concept of a chemical compound which is a prostanoic acid of the structure:

wherein A is -Cl-l Cl-l and X is trans-CH=CHCKk CH --CH,Ci-,

HO CH HO C ECH transCH=CH-C HO C ECH or A is cis-Cl-l=Cl-land X is transCH=CH-C HO CH,

HO C 'ECH The tangible embodiments of the second composition aspect of the invention possess the inherent general physical properties of being clear to yellow oils, are substantially insoluble in water and are generally soluble in organic solvents such as ethyl acetate and ether.

Examination of the compounds preduced according is CH CI-l R is ethynyl, A is CH CH and to the hereinafter described process reveals, upon in- B is trans-CH=CH; or R is ethynyl, A is cisCI-I=A Cl-land B is trans-CH=CH; and R is hydrogen, alkyl of from 1 to about 6 carbon atoms, alkali metal, or a pharmacologically acceptable cation derived from ammonia or a basic amine.

The tangible embodiments of the first composition aspect of the invention possess the inherent general physical properties of being clear to yellow oils, or crystalline solids, andwhen R is hydrogen are substantially frared, nuclear magnetic resonance, and mass spectrographic analysis, spectral data supporting the molecular structures herein set forth. The aforementioned physical characteristics, taken together with the nature of the starting materials, the mode of synthesis, and the elemental analyses, confirm the structure of the compositions sought to be patented.

The embodiments of the second composition aspect of the invention possess the inherent applied use charinsoluble in water and are generally soluble in organic acteristics of being useful as intermediates for the synsolvents such as ethyl acetate and ether. Examination of the compounds produced according to the hereinafter described process reveals, upon infrared, nuclear thesis of other compositions of the invention having bronchodilating activity, and, in addition, those compounds having a cis-S -en, a trans-l3-ene, a 9-hydroxy 3 group and having'in the l-position either a keto group or a hydrogen and hydroxy substituent or those having hydroxy and methyl substituents at the l5-positi0n are intermediates for the synthesis of 9-oxo-l5-hydroxy- IS-methyl-prostanoic acid.

The invention sought to be patented in its process as pect resides in the concept of a method of relieving bronchial spasm and facilitating breathing in warmblooded animals which comprises administering to a warm-blooded animal in need thereof an amount sufficient to relieve bronchial spasm and facilitate breathing in said warm-blooded animal ofa prostanoic acid'of the formula:

HO R

wherein R is methyl, A is cis-Cl-I=CI-l and B is transCI-I=CI-I; R is ethynyl, A is CH Cl-I and B is CH -CH R is ethynyl, A is CH -CI-l and B is transCII=ClI-; or R is ethynyl, A is cisCI-I=)\ CH and B is transCI-I=CH-; and R is hydrogen, alkyl of from 1 to about 6 carbon atoms, alkali metal, or a pharmacologically acceptable cation derived from ammonia or a basic amine.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In describing the synthesis of the compositions of the invention reference will be made to FIGS. 1 and 2 wherein the formulae representing the variousembodiments of the invention have been assigned Roman numerals for purposes of identification. FIG. 1 illustrates the synthesis of a specific embodiment of Formula I namely; 7-(2B-[(3RS )-3-hydroxy-3-methyl-trans-loctenyl]-5-oxo-Ia-cyclopentyl)-cis-5-heptenoic acid (IX) and the synthesis of specific embodiments of Formula II namely: 7-(5a-hydroxy-2B-[(3R)-3-hydroxytransl -octenyl]- l a-cyclopentyU-cis-S-heptenoic acid (VI); 7-(5B-hydroxy-2B-[(3R)-3-hydroxy-trans-loctenyl]-la-cyclopentyl)-cis-5-heptenoic acid (VII); 7-(5a-hydroxy-2B-[3-oxo-transl-octenyl1-1acyclopentyl)-cis-5-heptenoic acid (V); 7-(5a-hydroxy- 2B-'](3R5)-3-hydroxy-3-methyl-trans-l-octenyl1-1acyclopentyl)-cis-5-heptenoic acid (VIII); Sa-hydroxy- 2fl-[( 3R8 )-3 -hydroxy-3-methyl-trans-l -octenyl]- lacyclopentane-heptanoic acid (X); and the synthesis of the known compound 2B-[(3RS)-3-hydroxy-3-methyloctyl]-5 -oxo- I a-cyclopentaneheptanoic acid (XII).

FIG. 2 illustrates the synthesis of other embodiments of Formula I namely 2B-[(3RS)-3-ethynyl-3-hydroxytrans-l-octenyl1-5-oxo-la-cyclopentane heptanoic acid (XVI); 2B-[(3RS)-3-ethynyl-3-hydroxyoctyl1-5- oxo-la-cyclopentane heptanoic acid (XXII); and 7- (2B-[3-ethynyl3-hydroxy-trans-l-octenyl]-5-oxo-1acyclopentyl)-cis-5-heptenoic acids (XIX); and of other embodiments of Formula II namely: 7-(5B-hydroxy-2B- [3-oxo-trans-l-octenyl]-la-cyclopentyl)-cis-5-heptenoic acid (XVII); 2/3-[(3RS)-3-ethynyl-3-hydroxy octyl]-5B-hydroxy-la-cyclopentane heptanoic acid (XXI); ZB-l(3R5)-3-ethynyl-3-hydroxy-trans-loctenyl]-5B-hydroxy-la-cyclopentane heptanoic acid octenyl]-5B-hydroxy-1a-cyclopentyl)-cis-5-heptenoic acid (XVIII).

The starting materials in the synthesis of the compositions of the invention, namely IS-epi PGA (III), and PGA (IV) are well-known in the art. Forexample, l 5- epi PGA may be obtained from the coral Plexaura.

homomalla by a procedure as described by A Weinheimer :and R. Spraggins in Tetrahedron Letters, 59,

5185 (1969), and PGA may, if desired, be prepared from IS-epi PGA by an epimeriation procedure as described by Bundy et al. in Annals of the New York Academy of Sciences, 180, 76, (April 30,4971 So dium borohydride reduction of either III or IV yields a mixture of compounds VI and VII wherein the hydroxyl group at the Cl5 position will have an orientation corresponding to that of the starting material selected. Compounds VI and VII may, if desired, be separated by chromatography. Oxidation of V1 with chlorodicyanoquinone (DDQ) gives the enone V.

Treatment of V with methyl magnesium bromide gives. VIII which may be converted to IX by a Jones oxidation, or hydrogenated using tris-(triphenyl-phosphine).

rhodium (I) chloride to give X. Jones oxidation of X gives XI which may be hydrogenated using a palladium on charcoal catalyst to give XII.

If desired, compounds VII (1) chloride to give compound XIII. Oxidationof XIII using DDQ gives XIV. Reaction of XIV and. ethynyl magnesium bromide gives, XV. Jones oxidation of XV gives compound XVI.

DDQ oxidation of compound VII gives compound XVII. Reaction of XVII with ethynyl magnesium bro- I mide gives XVIII which is converted, if desired, to XIX.

Upon chromatography of XIX two products are isolated which are C--15 isomers, and which exhibit identical infrared, nuclear magnetic resonance, and mass,

spectra.

Hydrogenation of XVII using a palladium on charcoal catalyst gives compound XX which whentreated with ethynyl magnesium bromide is converted to XXI. I

Jones oxidation of XXI gives XXII.

It will be obvious to one skilled in the art that com-. pound VII or mixtures of compounds VI and VII may be substituted for compound VI as starting intermedi ate in the synthesis of IX and XII and that the intermediates thereto which correspond to V, VIII, and X will have the ring-hydroxyl group in a spatial orientation corresponding to that of the starting intermediate se-,

lected.

Similarly compound V] or mixtures of compound VI g and VII may be substituted for compound VII asstartric carbon atoms, and as a consequence these positions I can be either of two epimeric configurations. Thesymbol' where used in this specification is to indicate that both possible configurations at each particular position I is intended and is included within the scope of the invention.

di- I may be monohy- I drogenated using tris(triphenyl-phosphine)rhodium The esters of formula I (R is alkyl) are prepared by standard methods, such as for example, by treating a solution of the free acids with diazomethane or other appropriate diazohydrocarbons, such as diazoethane, l-diazo-2-ethylpentane, and the like. The alkali metal carboxylates of the invention can be prepared by mixing stoichiometrically equivalent amounts of the free acids of formula I, preferably in aqueous solution, with solutions of alkali metal bases, such as sodium, potassium, and lithium hydroxides or carbonates, and the like, then freeze drying the mixture to leave the product as a residue. The amine salts can be prepared by mixing the free acids, preferably in solution, with a solution of the appropriate amine, in water, isopropanol, or the like, and freeze drying the mixture to leave the product as a residue.

The term alkyl of from about 1 to about 6 carbon atoms" when used herein and in the appended claims includes straight and branched chain hydrocarbon radicals, illustrative members of which are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl, 2,3-dimethylbutyl, and the like. Alkali metal includes, for example, sodium, potassium, lithium, and the like. A pharmacologically-acceptable cation derived from ammonia or a basic amine" contemplates the positively charged ammonium ion and analogous ions derived from organicnitrogenous bases strong enough to form such cations. Bases useful for the purpose of forming pharmacologically-acceptable non-toxic addition salts of such compounds containing free carboxyl groups form a class whose limits are readily understood by those skilled in the art. Merely for illustration, they can be said to comprise, in cationic form, those of the formula:

wherein R R and R independently, are hydrogen, alkyl of from about I to about 6 carbon atoms, cycloalkyl of from about 3 to about 6 carbon atoms, monocarbocyclicaryl of about 6 carbon atoms, monocarbocyclicarylalkyl of from about 7 to about 11 carbon atoms, hydroxyalkyl of from about 1 to about 3 carbon atoms, or monocarbocyclicarylhydroxyalkyl of from about 7 to about 15 carbon atoms, or, when taken together with the nitrogen atom to which they are attached, any two of R ,R and R form part ofa to 6-membered heterocyclic ring containing carbon, hydrogen, oxygen, or nitrogen, said heterocyclic rings and said monocarbocyclicaryl groups being unsubstituted or monoor dialkyl substituted, said alkyl groups containing from about I to about 6 carbon atoms. Illustrative therefore of R groups comprising pharmacologically-acceptable cations derived from ammonia or a basic amine are ammonium, mono-, di-, and trimmethylammonium, mono-, diand triethylammonium, mono-, di-, and tripropylammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, l-methylpiperidinium, 4-ethylmorpholinium, l-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, l-n-butyl-piperidinium, 2-methylpiperidinium, l-ethyl-2-methylpiperidinium, mono-, di-

and triethanolammonium, ethylidiethanolammonium, n-butylmonethanolammonium, tris(hydroxymethyl)- methylammonium, phenylmonethanolammonium, and the like.

In practicing the method of the invention, the instant compositions can be administered in aa variety of 'dosage forms, the oral route being used primarily for maintenance therapy while injectables tend to be more useful in acute emergency situations. Inhalation (aerosols and solution for nebulizers) seems to be somewhat faster acting than other oral forms but slower than injectables and this method combines the advantages of maintenance and moderately-acute stage therapy in one dosage unit.

The daily dose requirements vary with the particular compositions being employed, the severity of the symptoms being presented, and the animal being treated. The dosage varies with the size of the animal. With large animals (about kg. body weight), by the oral inhalation route, with for example a hand nebulizer or a pressurized aerosol dispenser the dose is from about 5 micrograms to about micrograms, and preferably from about 10 to about 50 micrograms, approximately every 4 hours, or as needed. By theoral ingestion route, the effective dose is from about 1 to about 20 mg., preferably from about 5 to about 15 mg. up to a total of about 40 mg. per day. By the intravenous route, the ordinarily effective dose is from about 50 micrograms to about 300 micrograms, preferably about 200 micrograms per day.

For unit dosages, the active ingredient can be compounded into any of the usual oral dosage forms including tablets, capasules and liquid preparations such as elixirs and suspensions containing various coloring, flavoring, stabilizing and flavor masking substances. For compounding oral dosage forms the active ingredient can be diluted with various tableting materials such as starches of various types, calcium carbonate, lactose, sucrose and dicalcium phosphate to simplify the tableting and capsulating process. A minor proportion of magnesium stearate is useful as a lubricant. In all cases of course, the proportion of the active ingredient in said composition will be sufficient to impart bronchodilating activity thereto. This will range upward from about 0.000l% by weight of active ingredient in said composition.

For administration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute aqueous solution, preferably at concentrations of about 1 part of medicament to from about 100 to 200 parts by weight of total solution. Entirely conventional additives may be employed-to stabilize these solutions or to provide isotonic media, for example, sodium chloride, sodium citrate, citric acid, sodium bisulfite, and the like can be employed.

For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can also be used a dispersing agent such as oleyl alcohol. Suitable means to employ the aerosol inhalation therapy technique are described fully in US. Pat. No. 2,868,691 and 3,095,355, for ex- 7 ample.

The following examples further illustrate the best mode contemplated by the inventor of making the compositions of the invention.

EXAMPLE I 7-(5a-Hydroxy-2B-l (3R)-3-Hydroxy-Trans-1- Octenyl]-1a-Cyclopentyl)-Cis-5-Heptenoic Acid and 7-( B-Hydroxy-2B-[ (3R)-3-Hydroxy-Transl Octenyl]-1a-CyclopentyD-Cis-S-Heptenoic Acid An ice-cooled solution of 4.0 g. of 7-(2B-[(3R)-3- hydroxy-trans-l-octenyl]-5-oxo-la-cyclopent-3-enyl)- cis-S-heptenoic acid in l ml. of a 10:1 mixture methanol water is treated with 2.2 g. of sodium borohydride, and stirred at 25 for 7 hours. The mixture is concentrated under vacuum at 40, the residue diluted with water, acidified with acetic acid and the mixture partitioned with ether. After washing and drying, the extract is evaporated and the residue chromatographed on silica. Elution with 35% ethyl acetate-hexane affords the first title product as an oil, A 2.95, 3.4, 5.8, 7.1, 8.1, 8.8, 9.7, 10.3 t. NMR: 8 5.48 (M, 4, olefinic H), 4.62 (2, OH), 4.28 (M, 2, 9 and H) PPm. Mass spectrum: M* at m/e 338 (theory 338), M -H O at m/e 320.2331 (theory 320.2350).

Further elution with 40% ethyl acetate-hexane gives the second title product as an oil, A 3.0, 3.4, 5.8, 7.1, 8.1, 9.35,10.3 u. NMR: u 5.55 (M, 4, olefinic H), 4.58 (s, OH), 4.05 (M, 2, 9 and 15H) ppm. Mass spectrum: M at m/e 338 (theory 338). M H O at m/e 320.2384 (theory 320.2350).

EXAMPLE II 7-[5a-Hydroxy-2fi-(3-Oxo-Trar1s-l-Octenyl)-1a-- Cyclopentyl]-Cis-5-Heptenoic Acid A solution of 3.63 g. of 7-(5a-hydroxy-2B-[(3R-3- hydroxy-trans- 1 octenyl -1 a-cyclopentyD-cis-S-heptenoic acid in 250 ml. of dioxane is treated with 3.63 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and stirred at 55 for 40 hours under nitrogen. The solution is concentrated under vacuum at 40 and the residue chromatographed on silica. Elution with 30% ethyl acetate-hexane yields 1.8 g. of the title product as an oil, mfg- 3.0 (shoulder), 3.4, 5.8, 6.0 (shoulder), 6.15 h uld 7.1, 8.1, 10.2 )t. UV: M 232 mp. 12,100). NMR: 6 6.72 (dd, 1, J=5.3 and 15, 13-1-1), 6.08 (d, 1, J=15, 14--H), 5.40 (M, 2, 5 and 6-H), 4.25 (M, 1, 9-H) ppm. Mass spectrum: QM? at m/e 337 (theory 337), QM H O at m/e 319 (theory 319).

EXAMPLE III 7-(5a-Hydroxy-2B-[ 3RS )-3-Hydroxy-3-Methyl- Trans-1-Octenyl]-1a-Cydlopentyl)-cis-5-Heptenoic Acid An ice-cooled solution of 1.7 g. of 7-[5a-hydroxy- -(3-oxo-trans-l-octenyl)-1a-cyclopentyl]-cis-5-heptenoic acid in 150 ml. of tetrahydrofuran is treated with 15 ml. of 3M methyl magnesium bromide in ether dropwise over 10 minutes, under nitrogen. After stirring at 0 for 45 minutes, the mixture is added to ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing and drying, the extract is evaporated and the residue chromatographed on silica. Elution with 35% ethyl acetate-hexane af- I fords 1.07 g. of the title product as an oil, Afif'glO, 3.4,

5.8, 8.1,10.3 ,u.. NMR: 5 5.42 (M, 4, olefinic H), 5.12 (s, 3, OH), 4.20 (M, 1, 9H), 1.28 (S, l.5CH ppm. Mass spectrum QM -H O at m/e 335 (theory 335).

EXAMPLE IV 7-( 2,8-[ 3RS )-3-Hydroxy-3-Methyl-Transl Octenyl 4 5-Oxo-1a-Cyclopentyl)-Cis-5-Heptenoic Acid An ice-cooled solution of 1.02 g. of 7-(5oz-hydroxy -[(3RS)-3-hydroxy-3-methyl-trans-l-octenyl]-1acyclopentyl)-cis-5-heptenoic acid in ml. of acetone is treated dropwise with Jones reagent until the orange color persists. After stirring at 0 for 7% hour, the mix- I ture is treated with 5 ml. of methanol and dilute sodium bicarbonate until basic. The mixture is diluted with water, acidified with acetic acid and extracted with ether.

After washing and drying, the extract is evaporated and the residue chromatographed on silica. Elution :with

30% ethyl acetate-hexane gives 0.12 g. of the title product as an oil, A{,Z[3,3.0, 3.4, 5.75, 7.1, 8.15, 865,103 ;1.. NMR: 8 6.80 (s, 2, OH), 5.72 (M, 2, l3 and ,14H), 5.52 (M, 2, 5 and 6H), 1.30 (s, 15CH ppmqMass spectrum: QM at m/e 351 (theory 351); i

EXAMPLE V 5a-Hydroxy-2,B-[(3RS)-3-Hydroxy-3-Mlethyl-Trans-1- I Octenyll-la-Cyclopentane Heptanoic Acid A solution of 2.5 g. of 7-(5a-hydroxy-2B-,[(3RS)-3- at 25 and atmospheric pressure until 1 equivalentof hydrogen is absorbed. Evaporation of the solvent and silica chromatography of the residue with 45% ethyl:

acetate-hexane gives 1.878 g. of the title productas an oil, xfggggo, 3.5, 5.85, 6.85,,8.95,10.3 p" NMR:B 5.55 i

(M, 2, l3 and l4H), 4.98 (S, 3, OH), 4.32 (M, l, 9 -H) ppm. Mass spectrum: QM -2H O.at m/e 319.2636 (theory 319.2636).

EXAMPLE VI 2B-[ 3RS )-3-Hydroxy-3-Methyl-Trans -Octenyl]-5 Oxo-1a-Cyclopentaneheptanoic Acid An ice-cooled solution of, 1.795 g. of Sa-hydroxy-ZB- i 3RS )-3 hydroxy-3methyl-trans- 1 -octenyl]-1 acyclopentane-heptanoic acid in ml. of acetone is treated dropwise with Jones reagent until the orange color persists. After stirring at 0 for 25 minutes, the

mixture is treated with 10 ml. of methanol and dilute sodium bicarbonate until basic. Following dilution with water, the mixture is acidified with acetic acid and extracted with ether. The extract is washed, dried, evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate-hexane affords 0.33 gof V the title product as an oil, AQZ' ZQS (shoulder), 3.4,

5.75, 6.8, 8.6, 10.25 M. NMR: 8 6.22 (OH), 5.62 (M,

13 and 14H), 1.28, 1.28 Cl-1 ppm. Mass spectrum: QM*H O at m/e 335 (theory 335).

.EXAMPLE Vll 2B-[ 3R8)-3-1-1ydroxy-3-Methyloctyl]-5-Oxo-1a- Cyclopentaneheptanoic Acid EXAMPLE V111 5,B-Hydroxy-2B-[(3R)-3-Hydroxy-Trans-1-Octenyl]- la-Cyclopentaneheptanoic Acid A solution of 4.4 g. of 7-(5B-hydroxy-2B-[(3R)-3- hydroxy-trans-1-octenyl]-1 a-cyclopentyD-cis-S-heptenoic acid in 50 ml. of 1:1 benzene-ethanol is added to a prehydrogenated solution of 1.1 g. of tris-(triphenylphosphine) rhodium (I) chloride in 200 ml. of 1:1 benzene-ethanol and the mixture hydrogenated at 25 and atmospheric pressure until 1 equivalent of hydrogen is absorbed. Evaporation of the solvents and silica chromatography of the residue with 40% ethyl acetate-hexane affords 2.7 g. of the title produce as an oil, A22"; 3.05, 3.4, 5.85, 6.8, 8.1, 9.8,10.3 ,u. NMR: 8 5.58 (M, 2,13 and 14H), 3.95 (M, 2, 9 and 15H) ppm. Mass spectrum: M at m/e 340 (theory 340), M H O at m/e 322.2493 (theory 322.2505

EXAMPLE IX 5,8-Hydroxy-2/3-(3-Oxo-Trans-1-Octenyl)-1a- Cyclopentane Heptanoic Acid A solution of 2.7 g. of 5B-hydroxy-2B-[(3R)-3- hydroxy-trans-l-octenyl]-1a-cyclopentane heptanoic acid in 150 ml. of dioxane is treated with 2.7 g. of 2,3- dichloro-5,6-dicyano-1,4-benzoquinone and the mixture stirred at 75 for 18 hours under nitrogen. After cooling to 25, the mixture is filtered, diluted with ether, filtered again and washed with water. The ether solution is then extracted 4 times with aqueous saturated sodium bicarbonate and the aqueous extracts acidified with acetic acid and extracted with ether. The ether extract is combined with the original ether solution, evaporated and the residue chromatographed on silica. Elution with 40% ethyl acetate-hexane gives 1.42 g. of the title product as an oil, 1%{330 (shoulder), 3.4, 5.85, 6.0 (shoulder), 6.15, 8.4, 9.35,10.2 11.. UV: 1175113" 230 mp. (e 13,200), NMR: 8 6.8 (dd, 1, J=7.5 and 15, 13-H), 6.0 (d, 1, J=15,14H), 3.95 (M, 9H) ppm. Mass spectrum: QM at m/e 339 (theory 339).

EXAMPLE X 2B-[(3RS)-3-Ethynyl-3-Hydroxy-Trans-1-Octenyl]- SB-Hydroxy-la-Cyclopentane Heptanoic Acid A solution of 1.42 g. of 5B-hydroxy-2B-(3-oxo-trans- 1-octenyl)la-cyclopentane heptanoic acid in 30 ml. of tetrahydrofuran is added to an ice-cooled solution of ethynyl magnesium bromide (made from 13.3 ml. of

3M methyl magnesium bromide and excess acetylene) in 170 ml. of tetrahydrofuran and the mixture stirred at 0 for 15 minutes and at 25 for 3 hours. The mixture is diluted with aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing and drying, the extract is evaporated and the residue chromatographed on silica. Elution with 40% ethyl acetate-hexane affords 1.03 g. of the title product as an oil, Afifi'ilOS, 3.4, 5.8, 9.3, 10.3 11.. NMR: 6 5.95 (dd, 1, J=7.5 and 15,13-H), 5.4 (d, 1, J=15, 14-H), 3.92 (M, 1, 9-1-1), 2.58 (s, 1, acetylenic H) ppm. Mass spectrum: QM at m/e 365 (theory 365).

EXAMPLE x1 2B-[,(3RS)-3-Ethynyl-3-Hydroxy-Trans-1-Octenyl]-5- Oxo-la-Cyclopentane Heptanoic Acid An ice-cooled solution of 1.0 g. of 2B[(3RS)-3-ethynyl-3-hydroxy-trans-1 -octenyl]-5B-hydroxy-1 acyclopentaneheptanoic acid in ml. of acetone is treated with Jones reagent (3.9 ml.) over 20 minutes until the orange color persists. After stirring at 0 for k hour, under nitrogen, the mixture is treated with 10 ml. of methanol and dilute sodium bicarbonate until basic. Following dilution with water and acidification with acetic acid, the mixture is extracted with ether and the extract wadhed, dried and evaporated. Silica chromatography of the residue with 30% ethyl acetatehexane gives 0.27 g. of the title product as an oil, M111"; 3.05, 3.45, 5.8, 7.1, 865,103 u. NMR: 8 5.98 (dd, 1, J=7.5 and 15, 13-H), 5.55 (d, 1, .1=15, 14H), 2.60 (s, 1, acetylenic H) ppm. Mass spectrum: QM at m/e 363 (theory 363).

EXAMPLE XII 7-[5B-Hydroxy-2B-( 3-Oxo-Trans- 1 -Octenyl)- l a- Cyclopentyl]-Cis-5-Heptenoic Acid A solution of 0.51 g. of 7-(5B-hydroxy-2B-[(3R)-3- hydroxy-trans-l-octenyl1-1a-cyclopentyl)-cis-5 -heptenoic acid in 40 ml. of dioxane is treated with 0.51 g. of 2,3-dich1oro-5,6-dicyano-1,4-benzoquinone and the mixture stirred at 55 for 24 hours under nitrogen. The mixture is evaporated and the residue chromatographed on silica with 40% ethyl acetatehexane to obtain 0.38 g. of the title product as an oil, )t},,Z' 3.0 (shoulder), 3.4, 5.85, 6.0 (shoulder), 6.15 (shoulder), 8.1, 9.3, 10.2 11.. UV:)t "23l my. (6 14,050). NMR:: 6.85 (dd, 1, J=7.5 and l6,'131-1), 6.08 (d, 1, J=16, 14-1-1), 5.50 (M, 2, 5 and 6-1-1), 4.00 (M, 1, 9-l-1) ppm. Mass spectrum: M at m/e 336.2299 (theory 336.2299).

EXAMPLE XIll 5B-Hydroxy-2B-( 3-Oxo-Octy1)-1 a-Cyclopentaneheptanoic Acid A solution of 2.68 g. of 7-[5/3-hydroxy-2/3-(3-oxotrans-b 1 -octenvl)-1 a-cyclopentyl -cis-5 -heptenoic acid in 50 m1. of ethyl acetate is added to a prehydrogenated mixture of 0.67 g. of 10% Pd/C in 50 ml. of ethyl acetate and hydrogenated at 25 and atmospheric pressure until 2 equivalents of hydrogen are absorbed. The mixture is filtered, evaporated and the residue chromatographed on silica. Elution with 35% ethyl acetate-hexane affords 1.96 g. of the title product as an oil, X11135 3.0 (shoulder), 3.4, 5.8, 6.8, 7.05, 8.2 p.- NMRzS 6.35 (s, 2, OH), 3.95 (m, l, 9-H), 2.2-2.6 (M, 6,

, 1 1 CO-CH) ppm. Mass spectrum; QM'+H2O at m/e 323 (theory 323).

A solution of 1.86 g. of B-hydroxy-2B-(3-oxooctyl)-la-cyclopentane heptanoic acid in 30 ml. of tetrahydrofuran is added to a solution of ethynyl magne- 1 sium bromide (made from 18.0 ml. of 3M methyl magnesium bromide in ether and excess acetylene) in 220 ml. of tetrahydrofuran and the mixture stirred at 25 for 2 hours under nitrogen. Following dilution with aqueous ammonium chloride. solution and acidification with acetic acid, the mixture is extracted with ether. After washing and drying, the extract is evaporated and the residue chromatographed on silica. Elution with 40% ethyl acetate-hexane gives 1.54 g. of the title product as an oil, M";,'; }.05, 4.5, 5.8, 6.8, 90,107 .1.. NMR: 8 5.32 (s, 3, OH), 3.95 (M, l, 9-H), 2.48 (s, l, acetylenic H), 2.35 (M, 2, CO CH) ppm. Mass spectrum: QM 2H O at rn/e 331.2633 (theory 331.2336).

EXAMPLE XV 2B-[(3RS)-3Ethynyl-3-Hydroxyoctyl]-5-Oxo-1oz- Cyclopentane Heptanoic Acid An ice-cooled solution of 1.45 g. of 2f3-[(3RS)-3- ethynyl-3hydroxyoctyl1-5B-hydroxy-la-cyclopentaneheptanoic acid in 50 m1. of acetone is treated with Jones reagent (4.0 ml.) until the orange color persisted and the mixture stirred at 0 for 1% hour under nitrogen. The mixture is treated with ml. of methanol, dilute sodium bicarbonate until basic and dilutedwith water. After acidification with acetic acid, the mixture is extracted with ether and the extract washed, dried and evaporated. Silica chromatography of the residue with 30% ethyl acetatehexane gives 0.32 g. of the title product as an oil, MlJZlOS, 3.4, 4.7 (weak), 5.75, 6.8, 7.05, 8.6 11.. NMR:S 6.02 (M, OH), 2.48 (s, acetylenic H) ppm. Mass spectrum: QM -H O at m/e 347 (theory 347).

EXAMPLE XVI 7-(2B-[(3R8)-3-Ethynyl-3Hydroxy-Trans-1-Octenyl]- SB-I-Iydroxy-la-CyclopentyD-Cis-SHeptenoic Acid A solution of 9.95 g. of 7-[5/3-hydroxy-2B-(3-oxotrans-1-octenyl)-1oz-cyclopentyl]-cis-5-heptenoic acid in ml. of tetrahydrofuran is added to a solution of ethynyl magnesium bromide (made from 18.9 ml. of 3M methyl magnesium bromide and excess acetylene) in 270 ml. of tetrahydrofuran and the mixture stirred at for 1 hour under nitrogen. The mixture is diluted with aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. Following washing and drying, the extract is evaporated and the residue chromatographed on silica. Elution with ethyl acetate-hexane affords 1.55, g. of the title product as an oil, ",',3.05, 3.4, 5.8, 10.25 [L- NMR: 5 6.00 (dd, 1,J=7.5 and l5,13-H), 5.52 (M, 2, 5 and 6--H), 5.48 (d, J=l5, l4-H), 4.00 (M l, 9-H), 2.58 (5,1, acetylenic H) ppm.

EXAMPLE XVII 7-(2B-[(3R)3-Ethynyl-3Hydroxy-Trans-l-Octenyl] -5,- Oxo-la-Cyclopentyl)-Cis-5-Heptenoic Acid a I 7-( 2B-[ 3S )3Ethynyl-3-Hydroxy-Trans-1 -Octenyl]-5- Oxo-la-Cyclopentyl)-Cis-5Heptenoic Acid An ice-cooled solution of 1.415 g. of 7-(2B-[(3RS)- 3ethynyl-3hydroxy-transl -octenyl]-5B-hydroxy- 1 a cyclopentyl-cis-Sheptenoic acid in ml. of acetone is 1 treated with Jones reagent until theorange color persists and. the mixture stirred at 0 for A2 hourunder nitrogen. Themixture is treated with 10 ml. of methanol,

of a first product as an oil, MXZ' 305, 3.4,.5.75, 7.05,.

8.1, 8.6,10.25 ;1..NMR:8 7.22 (s, 2, OH), 5.3-6.4 (M, 4 olefinic H), 2.60 (s, acetylenic H) ppm..Mass spectrum: M at m/e 360 (theory 360), M -C H at m/e 334.2143 (theory 334.2193).

Continued elution afforded 0.04 g. of a second product, as an oil, which exhibits spectra identical tothat of the first product. On the basis of relative mobility in thin layer chromatography the second product is assigned the 3S configuration and the first product is assigned the 3R'configuration.

EXAMPLE XVIII Anesthetized (Dial-urethane) guinea pigs werea'rtificially respired at a constant positive air pressure (Starling miniature pump) andchanges in tidal air during inspiration were recorded, according to the method of Rosenthale et al., Int. Arch. PharmacoL, 172, 91.; (1968). The bronchoconstrictor agent acetylcholine (ACH) was administered at doses of 10 to 40 meg/kg. depending on each animals sensitivity to this" com-Q pound, and control responses to acetylcholine were thus established. Bronchoconstrictor agents raise the resistance of the lungs to inflation thereby decreasing the tidal air flow. 7-(2B-[(3S)-3-ethynyl-3-hydroxy transl -octenyl]-5-oxol a-cyclopentyl )-cis-5-heptenoic acid was then administered be aerosol, and the animals were then challenged again with acetylcholine, and the degree of inhibition of bronchoconstriction was thus determined. A minimum of two animals was used at each dose.

Results Mean Protection VS Total Aerosol Dose (mcg) ACH Bronchoconstriction Minimum of 2 animals per dose.

1 claim: 1. A compound of the formula:

wherein R is hydrogen, alkyl of from I to about 6 carbon atoms, alkali metal, or a pharmacologically acceptable cation derived from ammonia or a basic amine.

2. A compound as defined in claim 1 which is 23- [(3R5)-3-ethynyl-3-hydroxy-trans-l-octenyl1-5 -oxola-cyclopentane heptanoic acid. 

1. A COMPOUND OF THE FORMULA
 2. A compound as defined in claim 1 which is 2 Beta -((3RS)-3-ethynyl-3-hydroxy-trans-1-octenyl)-5-oxo-1 Alpha -cyclopentane heptanoic acid. 